ORGANIC LETTERS
Radical Cyclization of Sugar-Derived β-(Alkynyloxy)acrylates: Synthesis of Novel Fused Ethers
2000 Vol. 2, No. 9 1275-1277
Michiel A. Leeuwenburgh, Remy E. J. N. Litjens, Jeroen D. C. Code´e, Herman S. Overkleeft, Gijsbert A. van der Marel, and Jacques H. van Boom* Leiden Institute of Chemistry, P.O. Box 9502, 2300 RA Leiden, The Netherlands
[email protected] Received February 22, 2000
ABSTRACT
Tributyltin radical mediated cyclization of carbohydrate-derived β-(alkynyloxy)acrylates leading to highly functionalized cis- and trans-fused bicyclic ethers of various ring sizes is described. The efficacy of the radical cyclization is nicely illustrated in the iterative construction of a trans-fused tricyclic tetrahydropyran.
The development of synthetic procedures toward fused oxacycles, which are key structural elements in many marine toxins such as the brevetoxins1 and ciguatoxins,2 has received considerable attention over the past decade.3 In this respect, we4 and others5 recently showed the versatility of carbohydratederived dienes (A, Scheme 1) and enynes in the ring closing
Scheme 1
metathesis mediated synthesis of cis- and trans-fused bicyclic (B) as well as tricyclic ether systems. Some years ago, Lee et al.6 revealed that β-(alkynyloxy)acrylates could be converted into monocyclic ethers via tributyltin radical mediated cyclization and subsequent acidic destannylation. It occurred to us that this interesting two-step methodology could be 10.1021/ol0000408 CCC: $19.00 Published on Web 04/06/2000
© 2000 American Chemical Society
adopted for the conversion of appropriate carbohydratederived β-(alkynyloxy)acrylates C (see Scheme 1) into highly functionalized bicyclic ethers of type D. We here report the general usefulness of this approach in the construction of cis- and trans-fused bicyclic ethers of various ring sizes (i.e., D, n ) 0-3), as well as the feasibility (1) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.-C.; Golik, J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773. Shimizu, Y.; Chou, H. N.; Bando, H.; Van Duyne, G.; Clardy, J.-C. J. Am. Chem. Soc. 1986, 108, 514-515. Total synthesis: Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.; Sato, M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173 and references therein. (2) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380-4386. Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett. 1993, 34, 1975. Lewis, R. J.; Vernoux, J.-P.; Brereton, I. M. J. Am. Chem. Soc. 1998, 120, 5914. (3) For reviews about polycyclic ether synthesis, see: Alvarez, E.; Pe´rez, R.; Rico, M.; Rodrı´guez, R. M.; Martı´n, J. D. J. Org. Chem. 1996, 61, 3003. Mori, Y. Chem. Eur. J. 1997, 3, 849. (4) Leeuwenburgh, M. A.; Overkleeft, H. S.; Van der Marel, G. A.; Van Boom, J. H. Synlett 1997, 1263. Leeuwenburgh, M. A.; Kulker, C.; Duynstee, H. I.; Overkleeft, H. S.; Van der Marel, G. A.; Van Boom, J. H. Tetrahedron 1999, 55, 8253. Leeuwenburgh, M. A.; Kulker, C.; Overkleeft, H. S.; Van der Marel, G. A.; Van Boom, J. H. Synlett 1999, 1945. (5) Rainier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310. Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405. Maeda, K.; Oishi, T.; Oguri, H.; Hirama, H. Chem. Commun. 1999, 1063. Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372. (6) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993, 34, 4831.
of transforming C (n ) 1) into a tricyclic ether system via an iterative process. In the first instance, the transformation of the known7 perbenzylated R-1,2-anhydro-D-glucose 3 (Scheme 2) into
Scheme 2a
proceeded with virtually complete stereoselectivity to give the β-propargyl-C-glucoside 8.9 Subjection of the corresponding Michael adduct 9 to the same two-step procedure mentioned for the conversion of 5 into 7 gave the expected trans-fused pyranopyran 11 as the single diastereoisomer in 71% over the two steps. The high stereoselectivity and acceptable yield of the radical cyclization of 9 was an incentive to explore the feasibility of converting the known11 partially protected methyl R-D-glucoside 12 (Scheme 3) into the trans-fused
Scheme 3a
a
a Reagents and conditions: (a) NaCCH, ZnCl , THF, 0 °C to 2 room temperature, 85%; (b) ethyl propiolate, NMM, CH2Cl2, 98% 5, 95% 9; (c) Bu3SnH, AIBN, added over 5 h, toluene, 80 °C, 59% 6, 72% 10; (d) p-TsOH, CH2Cl2, 97% 7, 99% 11; (e) Bu3SnCHd CdCH2, n-BuLi, then ZnCl2, then 3, -50 °C to room temperature, 72%.
the respective cis-5,6- and trans-6,6-bicyclic ethers 7 and 11 was explored. To this end, 3 was treated with sodium acetylide in the presence of zinc chloride to give exclusively the R-ethynyl-C-glucoside 4.8,9 Hetero-Michael addition of 4 to ethyl propiolate under the influence of N-methylmorpholine gave the sugar-derived β-(alkynyloxy)acrylate 5 in 83% yield based on 3. The radical cyclization of 5 by syringe pump addition of Bu3SnH and AIBN in toluene at 80 °C led to the isolation of cis-fused 5,6-bicyclic vinylstannane derivative 6 in a yield of 59%. Acidic destannylation of 6 afforded in near quantitative yield 7, the stereochemistry of which was firmly established by NOESY spectroscopy. On the other hand, the trans-fused 6,6-bicyclic ether system 11 was also readily accessible from 3 by the following sequence of reactions. Ring opening of epoxide 3 with allenyllithium, generated in situ by transmetalation of allenyltributyltin10 with n-butyllithium, under the influence of zinc chloride (7) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661. (8) Leeuwenburgh, M. A.; Timmers, C. M.; Van der Marel, G. A.; Van Boom, J. H.; Mallet, J.-M.; Sinay¨ , P. G. Tetrahedron Lett. 1997, 38, 62516254. (9) Details on the synthesis of this and related C-glycosides from R-1,2anhydrosugars will be reported soon. 1276
Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2; (b) PPh3, CBr4, CH2Cl2, 82%-83% (two steps); (c) t-BuLi, THF, -50 °C, 76% 13a, 92% 13c; (d) DDQ, H2O, CH2Cl2, 79% 14a, 77% 14b, 77% 14c, 88% 14d; (e) ethyl propiolate, NMM, CH2Cl2, 94% 15a, 99% 15b, 97% 15c, 96% 15d; (f) I2, imidazole, toluene, 92% 16, 78% 19; (g) HCCLi ethylenediamine complex, DMSO, 74% 13b, 82% 13d; (h) H2, PtO2, EtOAc/hexanes; (i) LiAlH4, THF, 0 °C, 76% (two steps).
five- to eight-membered bicyclic ethers 20a-d (Table 1). Accordingly, 12 was subjected to Dess-Martin oxidation12 and the resulting aldehyde was transformed into alkyne 13a
Table 1. Formation of Five- through Eight-Membered Rings
a Conditions: (a) 2 equiv of Bu SnH and 0.25 equiv of AIBN, added 3 over 5 h to the acrylate in toluene at 80 °C, followed by stirring for 10 h; (b) 1.5 equiv of p-TsOH, CH2Cl2, 1.5 h. b Overall isolated yield of the cyclization and destannylation. c Bu3SnH and AIBN were added over 24 h.
Org. Lett., Vol. 2, No. 9, 2000
via a slightly modified two-step Corey-Fuchs procedure.13,14 Removal of the p-methoxybenzyl (MPM) group in 13a with DDQ was followed by hetero-Michael addition of alkynol 14a to afford five-membered ring precursor 15a in an overall yield of 47% from 12. The corresponding six-membered ring precursor 15b was also readily accessible by treatment of primary iodide 16, prepared by reaction of 12 with I2/PPh3/ imidazole in toluene, with lithium acetylide ethylenediamine complex. Subsequent deprotection of HO-4 in the resulting 13b and hetero-Michael addition of 14b afforded β-(alkynyloxy)acrylate 15b. On the other hand, known15 ethyl D-gluco-oct-6-enuronate 17 served as the starting compound for the 7,6- and 8,6-bicyclic ether precursors 15c and 15d. Thus, selective hydrogenation of the double bond in 17 under the influence of platinum(IV) oxide followed by reduction of the saturated ester with lithium aluminum hydride gave alcohol 18 (76%, two steps). Transformation of 18 into the corresponding aldehyde and sequential dibromoolefination and elimination yielded alkyne 13c in 76% over the three steps. Intermediate alkyne 13d was prepared from alcohol 18 by executing the earlier mentioned two-step protocol (cf. 12 f 13b) in an overall yield of 64%. Deprotection of 13c and 13d at the 4-positions and installation of the acrylate functionalities yielded 15c and 15d, respectively. The results of the ensuing tributyltin radical mediated cyclizations of 15a-d and subsequent acidic destannylations to afford compounds 20a-d are summarized in Table 1. First of all, it is of interest to note that the formation of the trans5,6 bicyclic ether 20a proceeded more efficiently than the cis-5,6 system 7. This may be explained by taking into consideration that the acrylate moiety in 15a, in contrast to acrylate 5, adopts a more favorable equatorial conformation. It is also evident that there is a dramatic drop in yield going from the seven- to eight-membered rings (20c to 20d). In this particular case, the desired product 20d could only be isolated in 8% yield and the major product proved to be the result of hydrostannylation of the triple bond (60-70%). Prolonging the time of addition (i.e., from 5 to 24 h) of Bu3SnH and AIBN in order to suppress quenching of the intermediate vinylic radical by Bu3SnH only led to a slight increase in the yield of 20d. An additional merit of the radical cyclization process is the formation of an exocyclic double bond. The latter feature offers the opportunity to install an equatorially oriented hydroxyl group, thus opening the way for an iterative radical cyclization process. The feasibility of this concept is demonstrated in the conversion of bicyclic 20b into the tricyclic system 26 (Scheme 4). In this respect, it was gratifying to establish that subjection of 20b to ozonolysis and in situ reduction of the intermediate ozonide with sodium borohydride was a highly efficient and stereoselective (10) Boaretto, A.; Marton, D.; Tagliavini, G. J. Organomet. Chem. 1985, 297, 149. (11) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1984, 2371. (12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769. (14) Butylation of the methylene of the MPM group was observed when n-BuLi instead of t-BuLi was used. (15) Stick, R. V.; Tilbrook, D. M. G. Aust. J. Chem. 1990, 43, 1643. Org. Lett., Vol. 2, No. 9, 2000
Scheme 4a
a
Reagents and conditions: (a) O3; NaBH4, MeOH/CH2Cl2 (7: 1), -70 °C to room temperature, 92%; (b) TBSOTf, i-Pr2EtN, CH2Cl2, 0 °C, 89%; (c) LiAlH4, Et2O, 0 °C, 91%; (d) Dess-Martin periodinane, pyridine, CH2Cl2; (e) CBr4, PPh3, CH2Cl2, 86% (two steps); (f) n-BuLi, THF, -50 °C, 92%; (g) TBAF, THF, 91%; (h) ethyl propiolate, NMM, CH2Cl2, 99%; (i) Bu3SnH, AIBN, added over 5 h, toluene, 80 °C, 90%; (j) p-TsOH, CH2Cl2, 97%.
process, giving equatorial alcohol 21 as the sole isomer, as evidenced by NOESY spectroscopy. Temporary protection of the newly formed secondary alcohol with a tert-butyldimethylsilyl (TBS) group and reduction of the ester in 22, followed by oxidation and a Corey-Fuchs procedure, gave alkyne 23 in 64% yield over the five steps. Fluoride-ion mediated desilylation and reaction of alkynol 24 with ethyl propiolate furnished bicyclic β-(alkynyloxy)acrylate 25, cyclization and destannylation of which afforded homogeneous tricyclic ether 26 in an overall yield of 87%. In summary, an efficient method for the preparation of functionalized fused ethers of various ring sizes by radical cyclization of sugar-derived β-(alkynyloxy)acrylates is presented. The versatility of this approach is highlighted by the iterative expansion of 20b to give 26 in an overall yield of 48% over 10 steps and nicely complements recently reported related radical cyclization protocols.16 At present, we are studying in detail whether an appropriately protected sugar can be extended at both the reducing and nonreducing end. Acknowledgment. We thank Fons Lefeber for recording the 2D-NMR spectra, Hans van den Elst for the mass spectra, and Han Peeters (University of Amsterdam) and Peter van Veelen for the high-resolution mass measurements. Supporting Information Available: General experimental procedures for the acrylation, radical cyclization, and acidic destannylation. Full characterization data for compounds 7, 11, 20a-d, and 26. This material is available free of charge via the Internet at http://pubs.acs.org. OL0000408 (16) Lee, E.; Tae, J. S.; Chong, Y. H.; Park, Y. C. Tetrahedron Lett. 1994, 35, 129. Evans, P. A.; Roseman, J. D. J. Org. Chem. 1996, 61, 2252. Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999, 40, 2811. 1277
